Infection with Leishmania amazonensis (La) can cause diverse forms of leishmaniasis in humans in the New World, and results in non-healing cutaneous lesions in most inbred mouse strains. Host factors responsible for this generalized susceptibility are poorly understood;however, it is clear that control of this infection relies on the induction of a strong Th1-type immune response. Evidence generated during the previous funding period has highlighted unique aspects of host-parasite interaction, and supports a novel hypothesis that this parasite not only suppresses activation of innate and Th1 responses via an IL-4-independent mechanism, but also takes advantage of the adaptive immune system for its propagation and persistence. This application is to seek continued support in three specific areas of research that are cohesively linked. First, we will examine whether susceptibility to La infection is due to defects at the level of dendritic cells (DC) via alteration of their antigen-presenting functions. Comparative studies will be conducted using a mouse strain that gives rise to different disease outcomes following infection with La and L. major. Secondly, we will focus on the La infection model and examine the impact of DC-stimulating agents on parasite-specific immunity and disease outcome. Studies employing cytokines, chemokines, and ligands for Toll-like receptors (TLR) will provide a mechanistic explanation of defects in La-infected DCs. Finally, we will examine the mechanisms and potential of modulating regulatory T cells for the control of La infection in naive and immunized mice. Approaches will include cell depletion prior to treatment/immunization and adoptive transfer of traceable cells to wild-type or gene-targeted knockout mice. Completion of this proposed study will aid in designing new control strategies for Leishmania and other chronic infections for which therapeutic/preventive interventions are not available.